1. Field of the Invention
This invention relates to a controlled release pharmaceutical composition that achieves a slow release of drug over an extended period of time and a method of therapeutically treating a patient with an illness employing the controlled release pharmaceutical composition.
2. Brief Description of the Background Art
Danazol is a synthetic androgen that inhibits the output of pituitary gonadotropins. Danazol is neither estrogenic or progestational and it depresses the output of both follicle stimulating hormone and luteinizing hormone. It is used in the treatment of endometriosis at a recommended therapeutic dose of 600-800 milligrams/day (mg/day) in two divided doses. In the treatment of fibrocystic breast disease, the therapeutic dose of danazol ranges from 100-400 mg/day in two divided doses. At a starting dose of 200 mg 2-3 times a day it is used in the management of migraine headaches. These high doses of danazol are required because the bioavailability of commercially available danazol is very low. The low bioavailability is due to the low solubility of danazol in aqueous medium and due to first pass hepatic metabolism, all well known by those skilled in the art. The high dose of danazol used in various therapies causes side effects such as weight gain, virilism, and decreased bone mineral content.
It is known to provide orally administrable drugs in tablet form for buccal administration to circumvent hepatic metabolism of the drug. The bioavailability of hepatically metabolized drugs, such as for example, but not limited to steroids, can be improved by buccal dosing. The buccal route of administration does not expose the drug to the metabolic enzymes on first passing via the intestines and through the liver during absorption.
Prior studies involving the oral, sublingual and buccal administration of steroids have been performed. Characterization and bioavailability of danazol-hydroxypropylxcex2-cyclodextrin coprecipitates, International Journal of Pharmaceutics, Vol. 128, pages 45-54 (1996), authored by Sherif I. Farag Badawy, Mahmoud M. Ghorab, and Christianah Moji Adeyeye (present Applicant), hereinafter referred to as Badawy I, describes the preparation and study of danazol complexed with aqueous hydroxypropyl xcex2-cyclodextrin (HPCD) solutions and administered via the oral route (non-buccally). Badawy I shows that the orally (non-buccally) administered danazol HPCD complex has increased solubility and higher dissolution rates in comparison to the commercially available oral (non-buccal) formulation of danazol (Danocrine(copyright), Sterling-Winthrop Pharmaceuticals, New York, N.Y.). Badawy I states that although both the danazol HPCD complex and Danocrine(copyright) showed relatively low absolute bioavailability due to presystemic elimination of danazol, the danazol HPCD complex showed a higher rate and extent of absorption via gavage administration over the commercially available formulation of Danocrine(copyright). Badawy I does not concern itself with overcoming the problems associated with buccal administration of drugs.
Bioavailability of danazol-hydroxypropyl-xcex2-cyclodextrin complex by different routes of administration, International Journal of Pharmaceutics, Vol. 145, pages 137-143 (1996), Sherif I. Farag Badawy, Mohmoud M. Ghorab, and Christianah Moji Adeyeye (present Applicant), hereinafter referred to as Badawy II, discloses the bioavailability of danazol HPCD complex using buccal and oral routes of administration. Badawy II employed a buccal administration of danazol via a rapidly dissolving adhesive patch. The adhesive patch was composed of danazol HPCD complex, hydroxypropyl cellulose/polycarbophil (carbopol 934)/polyethylene glycol (PEG) 400 in a 63.75:28.4:2.5:5.35 weight ratio. Badawy II states that the buccal absorption of danazol HPCD in the patch formulation across the mucosa was slow and the absorption phase long. Badawy II concluded that administration of the danazol HPCD complex in the rapidly dissolving patch formulation did not result in adequate buccal absorption of danazol and that further investigation was needed to allow for adequate buccal absorption.
U.S. Pat. No. 4,596,795 (Pitha) discloses the sublingual route of administration of steroids complexed with hydrophilic beta-cyclodextrin derivatives, namely hydroxypropyl betacyclodextrin (HPCD).
Bioavailability of testosterone using a bioadhesive tablet with penetration enhancers in dogs, World Meet. Pharm., Biopharm. Pharm. Technol., 1st, pages 179-80 (1995), J. Voorspoels, et al., hereinafter referred to as Voorspoels et al., discloses the administration of sodium taurodehydrofusidate, sodium deoxycholate, or hydroxypropyl beta cyclodextrin (HPCD) with testosterone in a buccal dosage form. Voorspoels et al. states that the use of HPCD did not improve the buccal administration of the steroid testosterone.
In spite of this background art, there remains a very real and substantial need for a controlled release pharmaceutical composition having greater bioavailability as provided by the instant invention for the therapeutic administration of drugs that effectively bypass presystemic metabolism and result in administration of a substantially lower dose to the patient.